In humans, telomeres are repeating strings of TTAGGG DNA sequences . The sequences protect chromosomal ends and maintain genomic stability. The gradual loss of telomeric DNA in dividing somatic cells contributes to senescence and apoptosis, indicating that telomere length can be used as a critical biomarker for cell aging. It is now increasingly recognized that telomere attrition also contributes to the pathogenesis of several age-dependent complex disorders including insulin resistance, hypertension, type 2 diabetes (T2DM), and cardiovascular disease (CVD). Although an increasing body of biological evidence indicates that both genetic and environmental factors may regulate telomere functions, human data that directly relate telomere length and its regulators (either biochemical or genetic) to the risk of T2DM development remain sparse. Moreover, small clinical studies have associated systemic inflammation with accelerated telomere erosion in human leukocytes. Our recent epidemiological work involving several large and well-characterized cohorts of men and women has shown that systemic inflammation and endothelial dysfunction play a significant role in the development of T2DM and CVD. Nevertheless, the magnitude and associations between serum markers of inflammation and endothelial dysfunctions with telomere length have never been investigated in a prospective study. As a direct follow-up to our previous work, we propose to investigate the role of telomere length and its bio-regulators in T2DM development in the ongoing Women's Health Initiative Observational Study (WHI-OS) where we have identified ~2,150 incident T2DM cases (1,100 whites, 600 blacks, 300 Hispanics, and 150 Asians) and 3,200 comparable controls (1:1 matching for Whites and 1:2 matching for minorities) of postmenopausal women, for a total of 5,350 participants. In particular, we will examine the interrelationship among biomarkers of inflammation and endothelial dysfunction with telomere length in relation to the development of T2DM. Further, we will examine whether single nucleotide polymorphisms (SNPs) on the genes coding for telomere-binding proteins and telomerase maintenance may explain the individual variability in telomere length and whether these SNPs would be significantly related to risk of developing T2DM among apparently healthy postmenopausal women at baseline. Because extensive prior molecular epidemiologic work has been completed in this well-characterized population, our proposal represents an exceptionally cost- effective means to advance our understanding of the etiology of T2DM in a short timeframe. PUBLIC HEALTH RELEVANCE: We propose to investigate the role of telomere length in type 2 diabetes (T2DM) development in a case-control study of 2,150 incident T2DM cases and 3,200 comparable controls (1:1 matching in Whites and 1:2 matching in minority groups) nested in the ongoing Women's Health Initiative Observational Cohort (WHI-OS) of postmenopausal women. In particular, we will examine the interrelationship among biomarkers of inflammation and endothelial dysfunction, as well as single nucleotide polymorphisms (SNPs) on the genes of telomere binding proteins and telomerase maintenance, with telomere length in relation to the development of T2DM in these well-characterized women. Extensive prior molecular epidemiologic works in this well-characterized population provide an exceptionally cost-effective means to evaluate this novel and promising study examining telomere length and its bio-regulators as predictors of T2DM in women. A better understanding of these relationships may lead to important insights into the complex biological mechanisms underlying aging, obesity, and T2DM, ultimately improving strategies for the prevention, diagnosis, and treatment of this prevalent condition in postmenopausal women.